The Optimal MMF Dose in Tacrolimus Treated Patients

Abstract

To the Editor: We appreciate the opportunity to respond to the Letter to the Editor of Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In their letter they propose a novel immunosuppressive strategy, aimed at treating de novo kidney transplant recipients with (very) low-dose tacrolimus and a higher mycophenolate mofetil (MMF) dose. The hypothesis of their prospective study is that reduced exposure to tacrolimus will result in an improved histology in 1-year protocol biopsies (less interstitial fibrosis and tubular atrophy), while the higher MMF dose (3 g daily) compensates for the lower tacrolimus exposure and will maintain efficacy. We feel that the observations in our analysis of three large, randomized-controlled trials (2Bouamar R Shuker N Hesselink DA et al.Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: A pooled analysis from three randomized-controlled clinical trials.Am J Transplant. 2013; 13: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) suggest that the currently targeted tacrolimus predose concentrations may be too high and that a further reduction of the target levels is possible without compromising efficacy. We agree that optimizing MMF exposure is likely to further improve the outcome. What the optimal MMF dose would be has been a matter of debate for some time. In the registration trials, MMF doses of 2 or 3 g per day were compared with placebo or azathioprine treatment. Patients in these studies were on full-dose cyclosporine (CsA) treatment. It may well be that in a setting of low-dose tacrolimus treatment (say target predose concentrations in the range of 3 ng/mL) higher MMF doses would offer a benefit. It is known that in tacrolimus-treated patients an MMF dose of 2 g/day will result in mycophenolic acid (MPA) exposure below the target in 25% of patients in the first month after transplantation (and in CsA co-treated patients this occurs in no less than 50%). Temporary intensified dosing has been suggested to avoid reduced MPA exposure in the early posttransplant phase (3Gourishankar S Houde I Keown PA et al.The CLEAR study: A 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.Clin J Am Soc Nephrol. 2010; 5: 1282-1289Crossref PubMed Scopus (48) Google Scholar). Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) propose a 3 g MMF dose in the first week, and in half of the patients this dose is maintained thereafter. Whether or not a prolonged duration of higher MMF dosing would offer a benefit when very low tacrolimus concentrations are targeted remains to be seen. One could expect more MMF-related toxicity in a substantial proportion of patients, as observed in an older MMF dose finding study in tacrolimus-treated patients (4Squifflet JP Bäckman L Claesson K et al.Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.Transplantation. 2001; 72: 63-69Crossref PubMed Scopus (122) Google Scholar). Therapeutic drug monitoring for MPA may identify patients with over-exposure, and in such patients, dose reductions may improve tolerability to the proposed regimen (5van Gelder T Therapeutic drug monitoring for mycophenolic acid is value for (little) money.Clin Pharmacol Ther. 2011; 90: 203-204Crossref PubMed Scopus (15) Google Scholar). The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Hesselink has received lecture fees from Astellas Pharma. Dr. van Gelder has received lecture fees from Astellas Pharma, and Roche. Dr. Bernasconi has received consulting fees from F. Hoffmann-La Roche Ltd, Basel, Switzerland. All other authors have no conflicts to declare.